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Vitamin D and
diabetes
mellitus:
an update – 2013
Vitamin D e diabetes melito: uma atualização – 2013
Luiz Henrique Maciel Griz1, Francisco Bandeira1, Mônica Andrade Lima Gabbay2, Sergio Atala Dib2, Eduardo Freese de Carvalho3
ABSTRACT
Vitamin D deiciency and diabetes mellitus are two common conditions and they are widely prevalent
across all ages, races, geographical regions, and socioeconomic conditions. Epidemiologic studies have shown association of vitamin D deiciency and increased risk of chronic diseases, such as can-cer, cardiovascular disease, type 2 diabetes, and autoimmune diseases, such as multiple sclerosis and type 1 diabetes mellitus. The identiication of 1,25(OH)
2D receptors and 1-α-hydroxilase expres-sion in pancreatic beta cells, in cells of the immune system, and in various others tissues, besides the bone system support the role of vitamin D in the pathogenesis of type 2 diabetes. Observational studies have revealed an association between 25(OH) D deiciency and the prevalence of type 1 dia-betes in children and adolescents. This review will focus on the concept of vitamin D deiciency, its prevalence, and its role in the pathogenesis and risk of diabetes mellitus and cardiovascular diseases. Arq Bras Endocrinol Metab. 2014;58(1):1-8
Keywords
Vitamin D; diabetes mellitus; pathogenesis
RESUMO
A deiciência de vitamina D e o diabetes melito são enfermidades comuns na população e são alta-mente prevalentes em todas as raças, idades, regiões geográicas e situação socioeconômica. Es-tudos epidemiológicos mostram uma associação entre hipovitaminose D com o aumento do risco de doenças crônicas, tais como câncer, doença cardiovascular, diabetes melito do tipo 2 e doenças autoimunes como a esclerose múltipla e o diabetes mellitus do tipo 1. A identiicação de receptores
da 1,25(OH)2 D e da expressão da 1 α-hidroxilase nas células betapancreáticas, em células do sistema imunológico e em uma variedade de células do organismo além do tecido ósseo, suporta o papel da vitamina D na patogênese do diabetes tipo 2 e do tipo 1. Esta revisão apresenta e discute o conceito de deiciência de vitamina D, sua prevalência e seu papel na patogênese e no risco de desenvolvi-mento do diabetes melito e doenças cardiovasculares. Arq Bras Endocrinol Metab. 2014;58(1):1-8
Descritores
Vitamina D; diabetes melito; patogênese
1 Endocrinology, Diabetes and Bone
Diseases Division of Agamenon Magalhães Hospital of Universidade Federal de Pernambuco
(UFPE), Recife, PE, Brazil
2 Endocrinology Division
and Diabetes Center of Universidade Federal de São Paulo, São Paulo, SP, Brazil
3 Public Health and Epidemiology
Division of UFPE, Recife, PE, Brazil
Correspondence to:
Luiz Henrique Maciel Griz M.D, PhD, F.A.C.E.
Estrada das Ubaias, 332, ap. 302 52061-080 – Recife, PE, Brazil luizgriz@globo.com
Received on Jan/10/2013 Accepted on Nov/28/2013
INTRODUCTION
V
itamin D deiciency and diabetes mellitus are twocommon conditions in the elderly population. Vitamin D deiciency is currently a topic of intense in-terest, and is widely prevalent across all ages, races, ge-ographical regions, and socioeconomic strata. Subopti-mal vitamin D status contributes to many conditions, including osteomalacia, osteoporosis, falls, and fractu-res (1,2). In addition, epidemiologic observations have associated low vitamin D status with an increased risk of non-musculoskeletal diseases, such as cancer (3), mul-tiple sclerosis (4), type 1 diabetes mellitus (5), type 2 diabetes mellitus (6) and cardiovascular disease (7).
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receptors. The characteristics of 1,25(OH)2D are those of a hormone, and consequently vitamin D is a pro-hormone, rather than a true vitamin.
Vitamin D is not only essential for maintaining bone health, but it also plays a role in several other biochemical mechanisms within the human body. The mechanism of action of the active form of vitamin D is similar to that of other steroid hormones and is mediated by its binding to vitamin D receptor (VDR). VDRs are found in most tissues, not just in those that participate in the classic actions of vitamin D such as bones, intestines and kidneys, and the enzyme responsible for converting 25 (OH)D to 1,25(OH)2D is also expressed in a variety of extrarrenal sites, such as endothelial cells, beta cells, and immune cells (9).
The number of subjects with type 2 diabetes mellitus
is rising, due to effect of age, growth of the population, sedentariness and, mainly, obesity. Although changes in lifestyle, particularly weight loss and physical activity, delay the progression of diabetes, weight loss is difi-cult to be achieved and maintaind. The identiication of easily modiiable risk factors is therefore urgently needed for primary prevention of diabetes. Certain nu-tritional factors, such as vitamin D are also believed to play a role, and it has been suggested that endemic low vitamin D status contributes to the increased preva-lence of diabetes mellitus. There is increasing evidence
that vitamin D metabolism affects the risk of diabetes. Studies in humans have shown that vitamin D supple-mentation in infancy reduces the risk of type 1 diabetes mellitus during early adulthood (10). Published studies
in animals identiied a pancreatic receptor to the ac-tive metabolite of vitamin D. As vitamin D modulates insulin receptor gene expression and insulin secretion, it is an interesting environmental candidate for type 2
diabetes mellitus (11).
This review will focus on the concept of vitamin D, its prevalence, and its role in the pathogenesis of
diabetes mellitus, its risks and complications.
CONCEPT AND PREVALENCE OF VITAMIN D
INSUFFICIENCY AND DEFICIENCY
The concept of normal 25(OH)D concentration is a challenge. It has been suggested that vitamin D deiciency be deined as a 25(OH)D below 20 ng/ mL, insuficiency as a 25 (OH)D of 21 – 29 ng/mL, and suficiency as a 25 (OH)D of 30 – 100 ng/mL (to convert to nanomoles per liter, multiply by 2.496) (12).
A meta-analysis of high-quality primary prevention randomized control trials (RCT) of vitamin D and fracture risk consistently found that antifracture eficacy started at 25(OH)D levels of at least 30 ng/mL (13).
The guideline, written by the Endocrine Society Task Force, reports that 25(OH)D levels of 30 ng/ mL or higher compared with 20 ng/mL provide increase beneits (14). In contrast, the Institute of Medicine (IOM) report, based on evidence from observational studies and recent randomized trials, suggests that a serum level of 20 ng/mL of 25(OH) D would protect 97.5% of the population against adverse skeletal outcomes (15). Hypovitaminosis D has become endemic owing to the insuficient ingestion of vitamin D in combination with the use of sun protection clothing and sunblocks. The prevalence of vitamin D deiciency has been reported with great frequency even in sunny regions of the world. Studies on the prevalence of hypovitaminosis D in Saudi Arabia, Australia, Turkey, the Arab Emirates and India have shown that 30%-50% of children and adults had 25(OH)D levels below 20 ng/mL.In Recife (latitude 10ºS), Pernambuco,Brazil, the prevalence of vitamin D deiciency in postmenopausal women was 8% for 25(OH)D values below 15 ng/mL and 43% for those below 25 ng/mL (16).
An observational study carried out in Italy in postmenopausal women revealed that vitamin D levels in postmenopausal women were lower in those with type 2 diabetes mellitus than in those in the control
group (39% vs. 25%) (17). A Japanese study evaluating
581 diabetic patients and 51 nondiabetic ones showed a prevalence of hypovitaminosis D (< 20 ng/mL) of 75% with no differences between the type 2 diabetic patients and the control group (18). A study carried out in United Kingdom evaluated the prevalence of hypovitaminosis D in type 2 diabetic patients in an Asian community and its impact on the control of glycemia (19). The results revealed that the prevalence of vitamin D (< 20 ng/mL) was > 80%, being more common in the diabetics than in the control group (83% vs. 70%;
p = 0.07), and that the glycated hemoglobin levels were higher in the women with vitamin D deiciency.
Vitamin D and insulin resistance
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pathogenesis of type 2 diabetes mellitus (20). In
animals it has been demonstrated that the secretion of pancreatic insulin is inhibited by vitamin D deiciency (21) and that in humans vitamin D deiciency is related to glucose intolerance and type 2 diabetes mellitus
(22). Hypovitaminosis D leads to a deiciency in the secretion of insulin and induces glucose intolerance (23), while its replacement with vitamin D reestablishes these abnormalities (24).
Vitamin D affects the function of beta cells in various ways. The active form of vitamin D exerts its effects by activating the nuclear vitamin D receptor (VDR). The binding of 1,25(OH)2D to the VDR leads to the transcription of genes regulated by 1,25(OH)2D. The effect of vitamin D on insulin synthesis and secretion is evidenced by the presence of the vitamin D response element (VDRE) in the human insulin gene promoter and transcriptional activation of the human insulin gene caused by 1,25(OH)2D (25).An indirect effect of vitamin D on beta cells may be mediated by its regulation in the extracellular concentration of calcium and the inlux of calcium through the beta cells (26).
Vitamin D may also affect insulin resistance through the renin-angiotensin-aldosterone system. It is believed that angiotensin II contributes to increased insulin resistance by inhibiting the action of insulin in the vascular tissue and skeletal muscle, leading to a decrease in glucose uptake (27). Data support the vitamin D-VDR complex as a potential regulator of renin activity in humans and polymorphisms in the VDR gene may be associated with the pathogenesis of type 2
diabetes mellitus by inluencing insulin resistance (28).
However, whether vitamin D may inluence insulin secretion and action is controversy. Although some studies found no association between serum 25(OH) D levels and parameters of insulin action (29), others have shown positive associations. In the Canadian Prospective Metabolism and Islet cell Evaluation (PROMISE) study cohort (30), three univariate analyses indicated a signiicant positive association between serum 25(OH)D and the insulin sensitivity index for the oral glucose tolerance test (IS-OGTT): r = 0.30, p < 0.001. A signiicant negative association was found between serum 25(OH)D and the homeostasis model assessment (HOMA-IR): r = -0.29, p < 0.001, as well as signiicant positive associations between serum 25(OH)D levels and the insulinogenic index/ HOMA ratio: r = 0.14, p = 0.002. In the multivariate regression analyses, serum 25(OH)D was a signiicant
independent predictor of insulin sensitivity and beta cell function across all models (31).
In HIV positive patients there is prolonged exposure to the HIV virus and anti-retroviral therapy (ART), and both have been associated with metabolic abnormalities and insulin resistance. Vitamin D deiciency has been reported to be higher in various age groups of HIV-infected individuals, ranging from 60% of adolescents and young adults with serum 25(OH)D levels of less than 10 ng/mL in the Netherlands (32) (40° N) to more than 80% of adults, with a mean age of 41 years, showing serum 25(OH)D levels of less than 18 ng/ mL in Italy (30° N). In a group of premenopausal HIV women with a mean age of 40 years living in the city of Recife (10° S), 60% of them with lipodystrophy, 80% with dyslipidemia and 38% with metabolic syndrome, we found a 41% prevalence of vitamin D deiciency using a cut point of 30 ng/mL for serum 25(OH)D. After full adjustments, total serum cholesterol levels and the duration of ART were independently associated with vitamin D deiciency (33).
Vitamin D and type 2 diabetes mellitus
Vitamin D deiciency appears to predispose individuals to becoming type 2 diabetics, and there is evidence from observational studies that suggests an association between low levels of vitamin D and a risk of type 2
diabetes mellitus.
A decrease in the concentration of vitamin D was reported in a population of Asians from Bangladesh resident in London at risk for type 2 diabetes mellitus
compared with individuals with no such risk and who also presented a higher prevalence of type 2 diabetes mellitus than a British Caucasian population (34).
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serum 25(OH)D and risk of type 2 diabetes in a simple model. However, the association was attenuated in the multivariate analysis, adjusting for potential risk factors for type 2 diabetes.
An analysis from the Nurse Health Study demonstrated that women with a mean ingestion of vitamin D greater than 800 IU per day had a 33% lower risk of type 2 diabetes mellitus than those whose daily
ingestion was less than 200 IU (35).
To determine the association between serum 25(OH) D and diabetes risk and whether it varies according to ethnicity, an analysis of data from the Third national and Nutrition Examination Survey (1988-1994) was carried out. In this cross-sectional survey of a nationally representative sample of the U.S population, 25(OH)D was available from 6,228 people (2,766 non-Hispanic whites, 1,736 non-Hispanic blacks, and 1,726 Mexican Americans), aged ≥ 20 years with fasting and/or 2-h plasma glucose and serum insulin measurements. The results showed an inverse association between vitamin D status and diabetes, possibly involving resistance, in non-Hispanic whites and Mexican Americans, but not in non-Hispanic blacks (36).
All this data suggests that hypovitaminosis D may be a major risk factor in glucose intolerance in some individuals, but not in all populations. One explanation for the lack of association could be the existence of a variable effect in the threshold between different ethnic groups. It is possible that a particular population may have a diminished sensibility to vitamin D or to the effects of the parathyroid hormone (PTH). A cross-sectional study performed on obese female adolescent Afro-Americans suggested that 25(OH)D concentrations < 15 ng/mL represent the threshold from which vitamin D deiciency produces a negative effect on insulin sensibility (37), and adolescents in NHANES III with serum 25(OH)D levels of less than 15 ng/mL were more likely to have elevated blood glucose levels than those with the highest 25(OH)D values (> 26 ng/mL) (OR, 2.5; 95% CI, 1.0-6.4) (38).
Unlike observational studies, experimental studies lack evidence to support the hypothesis that vitamin D supplementation reduces the risk of diabetes or glucose intolerance. In a meta-analysis (39) published in 2007, none of the six studies reviewed was able to demonstrate a signiicant change in glucose intolerance. However, three of the studies were of short duration (≤ 3 months), and two of these employed the active form of vitamin D (1,25-dihydroxyvitamin D3). In addition,
the primary outcome of these studies was not the effect of vitamin D supplementation on glucose metabolism. In the placebo-controlled Women’s Health Initiative (WHI), the use of calcium supplement of 1,000 mg per day and vitamin D3 400 IU per day failed to reduce the risk of progression to diabetes over a period of seven years (40). The null result may, however, be attributable to the use of a low dose of vitamin D in the active treatment group.
In a systematic review (41) of studies published in English using Medline up to the end of February 2011, a total of eight observational studies and 11 interventional studies were included, in order to ascertain the association between vitamin D status and the incidence of type 2 diabetes mellitus and the effect
of vitamin D supplementation on blood glucose results. The daily ingestion of > 500 IU of 25(OH)D reduced the risk of diabetes by 13% a against an ingestion of < 200 IU per day. Individuals with higher 25(OH)D levels (> 25 ng/mL) had a lower risk of developing type 2 diabetes than those in the group with 25(OH) D levels of < 14 ng/mL. In a post-hoc analysis of eight studies comprising individuals with normal glucose tolerance levels at baseline, and in three small studies (32-60) of patients with type 2 diabetes vitamin D supplementation had no effect on the blood glucose results.
To determine whether vitamin D supplementation, with or without calcium, improved glucose homeostasis in adults at risk for diabetes, a randomized, double-blind, placebo-controlled study (42) was conducted, assigned in a 2-by-2 factorial-design, in which patients were given either cholecalciferol (2000 IU once daily), or calcium carbonate (400 mg twice daily) for 16 weeks. The results showed that supplementation with cholecalciferol, but not with calcium, improved beta cell function and had only a marginal effect on attenuating the rise in glycated hemoglobin. However, supplementation with cholecalciferol does not improve glycemic control in diabetic subjects with normal serum 25(OH)D levels.
Vitamin D and cardiovascular disease
A growing body of evidence suggests that low levels of 25(OH)D may adversely affect the cardiovascular system (43).
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increased risk for myocardial infarction, stroke, heart failure, and peripheral arterial disease, and studies in rodents have shown that vitamin D protects against cardiac hypertrophy and myocardial dysfunction (44).
Several mechanisms may explain the link between vitamin D deiciency and cardiovascular disease. Vascular smooth muscle cells and endothelial cells express receptors for vitamin D and have the ability to convert circulating 25(OH)D into 1,25(OH)2 D (45).
In vitro, activated 1,25(OH)
2D suppresses renin gene
expression, and regulates the growth and proliferation of vascular smooth muscle cells and cardiomycytes (44,46).
Demographic data in a sample representative of the United States from the Third National Health and Nutrition Examination Survey revealed that 25(OH) D levels are associated with important cardiovascular disease risk factors. The prevalence of diabetes mellitus
(odds ratio 1.98), obesity (odds ratio 2.29), increased levels of triglycerides (odds ratio 1.47) and arterial hypertension (odds ratio 1.30) were all signiicantly greater in the lower quartiles of the 25(OH)D serum levels than in the higher quartiles (< 0.001 for all) (47). Pilz and cols. found an association of vitamin D deiciency with heart failure and sudden cardiac death (SCD) in a large cross-sectional study of patients referred for coronary angiography. After adjustment for cardiovascular risk factors, the hazard ratios (with 95% conidence intervals) for death due to heart failure and for SCD were 2.84 (1.20-6.74) and 5.05 (2.13-11.97), respectively, when comparing patients with severe vitamin D deiciency [25(OH)D < 10 ng/mL] with persons in the optimal range [25(OH)D > 30 ng/mL] (48). On the other hand, a systematic review and meta-analysis found (51 eligible trials of moderate quality) that 25(OH)D was associated with nonsigniicant effects on the patient-important outcomes of death [RR, 0.96; 95% conidence interval (CI), 0.93, 1.00;
P = 0.08], myocardial infarction (RR, 1.02; 95% CI,
0.93, 1.13; P = 0.64), and stroke (RR, 1.05;95%CI,
0.88, 1.25; P = 0.59) (49).
A study veriied the relationship between hypovita-minosis D and intimal medial thickening (IMT) of the common carotid artery, measured by ultrasonography among 390 type 2 diabetic patients. Hypovitaminosis D was deined as a serum 25(OH)D concentration ≤ 15 ng/mL and IMT as a focal thickening > 1.2 mm at the level of the common carotid artery. They found a strong inverse and independent the association between
serum 25(OH)D and carotid artery IMT. The patients with hypovitaminosis D (n = 130) had a marked in-crease in common carotid artery IMT (1.10 ± 0.15 vs.
0.87 ± 0.14 mm, p < 0.001) (50).
Despite a large number of cross-sectional studies and a limited number of clinical trials that evaluated 25(OH)D concentrations as a potential determinant of cardiovascular disease and type 2 diabetes, it remains uncertain whether improving vitamin D status would reduce risk of these conditions.
Vitamin D and type 1 diabetes mellitus
Type 1 diabetes mellitus (T1D) is caused by a
complex autoimmune process associated with altered humoral and cellular immunity. The autoimmune response involves both β-cell speciic autoantibodies and autoreactive pathogenic CD4 and CD8T cells iniltrating the pancreatic islets (insulitis). The pre-diabetic phase of T1D may have relapsing-remitting course that leads to slowly progressive pancreatic islet
β-cell failure. Progression occurs depending on the interplay between antigen spreading, β-cell proliferation and loss of regulatory T (Treg) cells.
In the last few years, intervention trials in new-onset T1D has been taken to silence and/or modulate this altered immune response. A growing body of evidence from animal and in vitro studies suggests
the potential of 25(OH)D to modulate the immune response: 1) the presence of VDR on human activated inlammatory cells, 2) the ability of 25(OH)D to inhibit lymphocyte proliferation and 3) the ability of activated macrophages to produce 1,25(OH)2D, expressing CYP27B1. Additionally, most tissues in the body have VDR, which are also expressed in activated T and B human lymphocytes.
Initial studies showed that 25(OH)D not only acts suppressing lymphocyte proliferation, but may also modify the Th1/Th2 cytokine proile, which might help to limit the potential tissue damage associated with Th1 cellular immune responses (51). However a subsequent analysis demonstrated that although in vitro 25(OH)D seems to support a shift from Th1 to
Th2, its effects in vivo on T cells are more complex,
showing both inhibition of Th1 and Th2 cytokines, and reduced levels of Th1 cells.
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cells, inducting Treg cells and reducing chemokine production by islet cells (52). Treg cells exert suppressor rather than effector functions, and it seems that the differentiation of Treg is an important mechanism linking 1,25(OH)2D and adaptive immunity. The immunosuppressive mechanism is probably mediated by the induction of tolerogenic antigen presenting cells (like dendritic cells), increased IL-10 secretion and the expression of Toll-like receptor 9 (TLR9) by Tregs, suggesting a novel link between innate and adaptive immune response.
It also has been reported that exposition of human
β cell to 1,25(OH)2D protects them from death by reducing expression of MHC class I molecules, inducing expression of anti-apoptotic A20 protein and decreasing expression of FAS (that regulates activation-induced cell death) (53).
In vivo studies have shown that 1,25(OH)
2D
inhibits the expression of inlammatory cytokines in monocytes, such as IL-6, TNF-alfa, IL-8, and IL-12 in normal individuals. The inluence of this vitamin on cytokine production by lymphocytes may be another important link between the 25(OH)D and the immune system (54). Other facets of T-cell function may also be affected by the hormone, such as the homing of T cells to speciic tissues. The studies suggested that 1,25(OH)2D acts inhibiting migration of T cells to lymph nodes.
There are data showing that 25(OH)D supplemen-tation to offspring during infancy, as well as dietary exposure during pregnancy, was associated with a re-duced risk of human type 1 diabetes. Children who took 2000UI regularly had a RR of 0.22 (0.05-0.89), while children suspected of having rickets during the irst year of life had a RR of 3.0 (1.0-9.0) risk of T1D (10). It is interesting to observe that in Finland, while the recommended dosage of 25(OH)D has decreased gradually in the last few decades, associated with a de-crease in compliance to supplementation recommenda-tions, there was an increase in the incidence of T1D. Together with the observation that incidence rates of T1D tended to be higher at higher latitudes in both hemispheres, the association of ultraviolet B irradiance with risk of T1D was observed in 51 regions world-wide, which raises the possibility of 25(OH)D having a role in the development of the disease. In addition, a number of observational studies have revealed an as-sociation between 25(OH)D deiciency, and the
prev-alence of T1D in children and adolescents compared with non-diabetic individuals (55).
Another piece of evidence of the complex role of 25(OH)D is the extensive genetic analyses linking the polymorphic variation in the genes for several components of the 25(OH)D metabolic and signaling system to T1D. Some speciic VDR gene haplotypes appear to protect against diabetes, while polymorphisms in the CYP27B1 gene have been shown to affect diabetes susceptibility (56,57). Given the evidence that variation in the CYP27B1 etiologically contributes to T1D risk, other genes that control vitamin D metabolism are also biologically plausible candidates, and should be studied. In a clinical setting, two recent trials found no signiicant effect of 1,25(OH)2D on the preservation of β-cell function after type 1 diabetes onset (58,59). Nevertheless, the dose and mechanistic action of vitamin D are still under discussion. On the other hand, in a randomized, double-blind, placebo-controlled trial in new-onset T1D, we studied the effect of 2000 IU of 25(OH)D on peripheral cytokine levels, Treg cells and the decline of residual β-cell function. We found that the cumulative incidence of progression to undetectable (≤ 0.1 ng/ml) fasting serum C-peptide during the 18 months of follow-up reached 18.7% in the 25 (OH)D group, and 62.5% in the placebo group (P = .012) while stimulated C-Peptide reached this level in 6.2% of the 25(OH)D and 37.5% of placebo group (P = .047). We also found a tendency to increase IL-10 and Treg cells (CD4+CD25+Foxp3), which might
have contributed to the less progressive β-cell decay in the 25(OH)D group (60).
In any case, further studies based on large patient cohorts are needed to show whether the administration of 25(OH)D or 1,25(OH)2D signiicantly reduces the risk of T1D or contribute to the preservation of C-peptide after the diagnosis.
CONCLUSIONS
There is evidence that vitamin D deiciency leads to glucose intolerance and predisposes to type 2
diabetes mellitus, while the restoration of vitamin D
levels may reduce the risk of type 1 diabetes mellitus.
Despite observational studies showing a strong association between vitamin D deiciency and diabetes mellitus, randomized clinical trials with vitamin D
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supplementation, thereby not permitting any deinitive conclusions. Questions persist about the optimal level of 25 (OH)D to prevent the risk of developing diabetes mellitus. However, a large long-term clinical trials are
needed to clarify these issues. Vitamin D is inexpensive and should a trial conirm its beneit in the prevention of diabetes, it will have a major impact on public health.
Disclosure: no potential conlict of interest relevant to this article was reported.
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